The proposed investigations are designed to increase our understanding of the ecological basis of natural selection and of the mechanisms of evolution at the protein level. A theoretical and experimental examination is to be made of the relationship between the factors regulating population numbers and genotypic fitness. An array of models for resource and predator limited growth, competition and selection have been developed for microbial populations. During the course of these investigations these models are to be extended and the assumptions upon which they are based and the hypotheses generated from them are to be tested with experimental populations of Escherichia coli and phage. Using this approach realistic and predictive models of population regulation and selection are to be generated for these organisms. Primary consideration is to be given to population regulating mechanisms which lead to stable equilibria for multiple species or genotypes and of the effects of environmental factors on relative fitness. An experimental examination is to be made of the relationship between protein variation and selection in Escherichia coli populations. Two proteins of known in vivo function are to be used, tryptophane synthetase and B-galactosidase. Functional variants for these proteins are to be obtained by reverse mutation from negative mutants and from a survey of laboratory and natural populations of these species. An extensive fitness testing program is to be performed to determine the relationship between functional variation of these proteins and allelic fitness. Consideration shall also be given to the relationship between the in vitro catalytic efficiency of these proteins and fitness, and the effects of environmental factors on selection at the loci for these proteins.